The gut harbors trillions of microbes that live in equilibrium with the immune system. Disruption in this relationship, either by improper immune cell activation or changes in the microbiome, can result in chronic intestinal inflammation with progression to inflammatory bowel disease. The microbiota is also essential for the proper development of both the systemic and mucosal immune systems, as mice devoid of microbes have significant defects in innate and adaptive immune cell development and function. T regulatory cells (Tregs) play a critical role in maintaining gut homeostasis by controlling inflammatory responses and thus fostering host-microbiota co-existence. While recent studies have identified specific microbial species that influence Treg development, very little is known about how Tregs affect gut microbial community dynamics. The aims of this proposal are to define the contribution of Tregs to gut microbiota membership and function, determine the mechanism by which Tregs affect microbiota dynamics, and delineate the microbiota's effects on Treg cell persistence, function and stability. These studies will combine classic microbiology, immunology and computational biology approaches. This proposal will provide insights into how Tregs affect the microbiota to promote healthy states of gut homeostasis, as well as how perturbation of the microbiota affects Treg cell development, function and plasticity. Changes in the composition of the gut microbiota have been linked to the development of inflammatory bowel disease, type 1 diabetes and obesity. Therefore understanding how alterations in the immune system affect microbial community dynamics is of great interest for developing effective immunotherapies. The experiments proposed in this study may provide critical insight into how Tregs affect the gut microbiota, which will be important not only for the development of Treg-based immunotherapies and inflammatory bowel disease, but also for understanding the consequences of antibiotics exposure for human health. PUBLIC HEALTH RELEVANCE: Changes in the composition of the gut microbiota have been linked to the development of inflammatory bowel disease, type 1 diabetes and obesity. Therefore understanding how alterations in the immune system affect microbial community dynamics is of great interest for developing effective immunotherapies. The experiments proposed in this study may provide critical insight into how T regulatory cells (Tregs) affect the gut microbiota, which will be important not only for the development of Treg-based immunotherapies and inflammatory bowel disease but also for understanding the consequences of antibiotics exposure for human health.